DESCRIPTION (provided by candidate): The recent identification and characterization of a number of different murine models of inflammatory bowel disease have greatly enhanced our understanding of IBD and its pathogenesis. It is now clear that both immune regulation in the gut associated lymphoid tissue and the intestinal luminal flora are central to the development of disease. However we still do not understand how the inflammatory process is initiated, what it is directed against, and what factors govern the establishment of chronic disease. Experiments proposed in this application address the hypothesis that luminal bacterial products (bacterial toxin and bacterial DNA) play a role in triggering and/or regulating intestinal inflammatory and immune response to commensal bacteria, by breaking epithelial barrier function and/or dysregulating mucosal immune response. We propose to address these questions using novel in vivo and in vitro model systems. We will utilize a previously characterized model of adoptive transfer of ovalbumin (OVA) specific T cells from TCR transgenic mice. A model antigen OVA will be presented in a bacterial (E. coli) antigen delivery system. We will explore the role of bacterial toxins as triggering agents to alter intestinal permeability and barrier function, enhancing mucosal immune response to luminal bacterial antigens and causing intestinal inflammation. The advantage of the model proposed in this application is that it examines mucosal immune responses to physiologically relevant antigens in immunocompetent mice. In parallel, we will explore the cellular and molecular mechanisms by which bacterial products alter epithelial barrier function in the context of luminal bacterial exposure using T84 epithelial cell monolayer model. The experiments proposed should provide new insight into the mechanism by which luminal stimuli trigger the chronic intestinal inflammation that characterizes IBD and may suggest new avenues for treatment. This project will be co-sponsored by two well-established experts in the fields of microbial pathogenesis, cell biology and intestinal inflammatory diseases: Drs. Beth McCormick and Daniel Podolsky. The three-year K01 Award will provide the candidate with an essential period of advanced training and career development that will significantly enhance his transition to becoming an independent research investigator in the fields of gastrointestinal cell biology, microbial pathogenesis and mucosal immunology.